The primary goal of this proposal is to explore the hypothesis that the Notch pathway plays an important role in the development of diabetic nephropathy. We found via large scale genome screening that Notch pathway proteins are regulated in animal models of diabetic nephropathy. In vitro studies showed that the hyperglycemic milieu activates the Notch pathway and this activation leads to the dysfunction of glomerular cells. These observations suggest that the Notch pathway plays an important role in mediating diabetic complications. The specific aims of the proposal are to: Aim one is to characterize the molecular mechanism of glucose induced Notch pathway activation in podocytes. In the second specific aims we will determine the role of Notch pathway activation in glucose induced podocyte dysfunction. We will achieve this aim via genetic manipulation of Notch signaling. Under the third specific aim we will determine the in vivo functional role of glomerular epithelial Notch in mediating the development of diabetic nephropathy via the use of genetically engineered animals. In the long-term, this work will elucidate molecular signaling mechanisms determining specific, context dependent cellular responses, such as apoptosis and growth arrest that may be triggered by hyperglycemia in different cell types.